Acute mesenteric ischemia and COVID-19: an integrative review of the literature

ABSTRACT The novel coronavirus disease 2019 (COVID-19) has spread rapidly around the world after the first cases were reported in December 2019 in China. Despite the prevention of the symptoms presented, extrapulmonary manifestations were identified. In particular, there was an increase in cases of Acute Mesenteric Ischemia (AMI), raising its incidence to 1.9%-3.8% in infected patients. The aim of this study was to investigate the existence of an association between IMA and COVID-19 through the literature. An Integrative Literature Review was carried out. The research question was “mesenteric ischemia in patients with COVID-19: coincidence or association?”. After searching the database and applying the inclusion and exclusion criteria, 44 were selected for analysis. COVID-19 was confirmed by RT-PCR and imaging tests, gastrointestinal manifestations, alterations and primarily tomographic imaging findings were identified. Most patients were accelerated to laparotomy. As explanations include direct endothelial and injury by the binding of the ACE-2 virus, between hyperinflammation and hypercoagulability, dysregulation of the renin-angiotensin-aldosterone system and factors associated with the severity of the virus. IMA is an emergency with high associated morbidity and mortality, these cases may be a consequence mainly of the thromboinflammatory mechanism associated with SARS-CoV-2. An early diagnosis, diagnosis and diagnoses are crucial to clinical treatment; an assessment regime should be considered in accordance with current evidence and guidelines.

Despite being an uncommon cause of abdominal pain, AMI is a surgical emergency that consists of an abrupt interruption of intestinal blood flow.It is subdivided into mesenteric ischemia of non-occlusive and occlusive causes (mesenteric arterial embolism, mesenteric arterial thrombosis, and mesenteric venous thrombosis), whose overall mortality ranges from 50-80%, requiring immediate diagnosis and intervention due to the rapid clinical deterioration of patients [10][11][12] .
Exact answers about a certain thromboinflammatory mechanism triggered by SARS-CoV-2 [13][14][15] that possibly leads to AMI are still scarce.It is postulated that the pathogenesis of mesenteric ischemia secondary to COVID-19 is multifactorial: 1) Endothelial dysfunction resulting from expression of the Angiotensin-Converting Enzyme-2 (ACE-2) receptor, the cellular entry pathway of SARS-CoV-2, not only in alveolar cells, but also in vascular endothelium and intestinal cells 13,16,17 ; 2) State of hypercoagulability directly related to the inflammatory response, with activation and exacerbated expression of prothrombotic factors that lead to the formation of fibrin clots 15,16,[18][19][20] ; and 3) Factors related to severe COVID-19 conditions -blood stasis and hemodynamic disorders -, such as stimulation of thrombosis and ischemia 9,12 .
In this context, considering the epidemiological impact brought by SARS-CoV-2 and the high rate of complications and mortality of mesenteric ischemia itself, this study aimed to investigate the existence of an association between Acute Mesenteric Ischemia and COVID-19 through an analysis of the currently available literaturel.

METHODS
We carried out an Integrative Literature Review based on the following steps: identification of the problem with the elaboration of a research question; literature search; evaluation and analysis of data; and presentation of the review with its synthesized results and listed limitations 21,22 .The guiding question of the study was "mesenteric ischemia in patients with COVID-19: coincidence or association?".
We performed the bibliographical research in the PubMed database and the descriptors used were "Mesenteric Ischemia" and "COVID-19", both previously identified in MeSH and DeCS.We added the Boolean operator "AND" between the two terms, resulting in the combination: "'Mesenteric Ischemia' AND COVID-19".
We applied no language restrictions.

Eligibility criteria
We included original studies, reports, or case series, published between January 2020 and July 2022, in any language, that presented cases of acute mesenteric ischemia with previously or concomitantly diagnosed COVID-19 disease.We excluded articles with duplicate cases, meetings abstracts, studies without full text available, or pre-prints.
We identified 94 studies in the initial search.
After reading the titles and abstracts, we excluded 46 of them and pre-selected the remaining 48 for full text analysis.After complete reading, we excluded four of them, the final sample consisting of 44 studies (Figure 1).For data collection and organization, we used an adapted instrument, and the critical analysis of the included studies was carried out using the criteria of reduction, display, and comparison of data 21 .Finally, we synthesized and condensed the results in a table (Table 1).
In the series of cases proposed by Sarkardeh et al., 54% of the patients had no previous comorbidities and the mortality rate due to intestinal ischemia was 62.5% 53 .

DISCUSSION
The results of this review are suggestive of an association between Sars-CoV-2 infection and mesenteric Furthermore, despite the challenges in analyzing and synthesizing different primary sources 21 , we also find it  63 .
Endothelitis induced by COVID-19 occurs due both to direct viral involvement, given the existence of a tropism of SARS-CoV-2 to human endothelium, and to the host's response to the infection 13,[15][16][17][18]63 . Thi association stimulates a procoagulant and hyperinflammatory state, capable of triggering excessive thrombin production and inhibiting fibrinolysis, resulting in vascular dysregulation and consequent organ ischemia 16,63 .
SARS-CoV-2 enters the host cell through the interaction between its spike protein and the ACE-2 entry receptor and the coexpression of proteases, such as transmembrane serine 2 (TMPRSS2), is essential for this invasion process 13,16,17 .Vascular endothelial cells express a large number of ACE-2, which have also been found in tissues such as lung, liver, stomach, intestines, and kidney 13,17 .This finding brings an alert to the systemic complications of a virus that does not have only one pulmonary route in the body and justifies the histopathological evidence of tissue damage found in the analyzes of resected intestinal segments.

Thromboinflammation
Hyperinflammation and hypercoagulability are closely related during SARS-CoV-2 infection: a systemic, exacerbated, and persistent inflammatory response among infected patients, entitled "cytokine storm" 15,16,19 , is capable of causing a systemic imbalance in physiological anticoagulant pathways, driving the abnormal formation of clots, reduction of fibrinolysis, and even more endothelial injury with recruitment of inflammatory cells and platelet hyperactivation 15,18 .
The main cytokines described are interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) and they have been observed at high levels in patients with COVID-19, especially in the most critical ones 16,19 .

Dysregulation of the Renin Angiotensin Aldosterone System
RAAS imbalance during COVID-19 constitutes another pathophysiological mechanism that induces thrombosis, due to the negative regulation of the ACE-2 receptor 18,19 .Physiologically, it converts Angiotensin II (ANG-2) into Angiotensin 1-7, an important vasodilator involved in hydroelectrolytic balance and vascular permeability, with antithrombotic and antiproliferative properties 16 .Since Sars-CoV-2 binds to ACE-2 to enter target cells 13,16,17 , its dysfunction leads to reduced cleavage of ANG-2 into Angiotensin 1-7 and consequent increase in its expression in the organism 16,18,19 .ANG-2 acts as a potent vasoconstrictor and contributes to the hypercoagulable state.Elevated levels of ANG-2 have been seen in patients with COVID-19 19 .

Factors related to the severity of COVID-19
Blood stasis at the expense of prolonged immobilization of hospitalized patients, mainly in the ICU 14 , is also a cofactor for thrombosis due to localized hypoxia 13,64 , and when associated with endothelial injury and hypercoagulability, composes the well-known Virchow's Triad, directly related to CAC 14 .Hypoxia in these patients stimulates thrombogenesis not only by increasing blood viscosity, but by directly activating signaling pathways that regulate coagulation (hypoxiainducible transcription factors) and indirectly by inducing pro-inflammatory mediators 64,65 .Finally, hemodynamic instability, such as hypovolemia or sepsis, can lead to Non-Occlusive Mesenteric Ischemia (NOMI) due to reflex splanchnic vasoconstriction [66][67][68] .
Silva Acute mesenteric ischemia and COVID-19: an integrative review of the literature

2) Acute Mesenteric Ischemia
The intestine can withstand a reduction of around 75% in its blood supply for up to 12 hours, due to the wide network of existing mesenteric collaterals 11,12 .

Mesenteric arterial thrombosis
Arterial thrombosis occurs in approximately 25% of AMI cases 11,12 .The main risk factor is the presence of previous chronic atherosclerotic disease, and the others are correlated with it, such as dyslipidemia, hypertension and diabetes 11,12,66 .
However, during the search for cardioembolic sources or pre-existing atherosclerosis via imaging tests, no finding justified the AMI of the patients in our series, not even those with a previous diagnosis of atrial fibrillation 58 , which, it is worth noting, were on anticoagulation regimen.Thus, even though embolic events may occur, given the clinical diversity and background of patients, the reports (Table 1) strengthen the evidence that SARS-CoV-2 is associated with the acute development of thrombosis and not embolism 58 .

Non-occlusive mesenteric ischemia
NOMI is seen in 20% of patients with AMI and carries with it a high mortality rate, since it primarily affects the most severe patients 11,67 .Its pathogenesis is still poorly understood, usually being a consequence of splanchnic vasoconstriction in response to reduced mesenteric blood flow as a way to ensure perfusion of other vital organs, thus leading to hypoxia and intestinal ischemic injury 11,12,[66][67][68] .Some predisposing factors are hypovolemia, hypotension, sepsis, and use of vasoactive drugs 11,12,67 .

Mesenteric venous thrombosis
Mesenteric venous thrombosis is responsible for less than 10% of AMI cases 11,12 .However, during this review, it and arterial thrombosis were the most prevalent causes of ischemia concomitant with COVID-19 and, interestingly, there was a case of a patient who simultaneously presented with SMA and SMV thrombosis 25 .Venous obstruction by the thrombus results in intestinal wall edema, increased vascular resistance, and consequent mesenteric ischemia due to reduced arterial blood supply 11,12 .The already discussed components of the Virchow's Triad elucidate the development of venous thrombus.Other causes of hypercoagulability, such as certain hereditary diseases 12 , were not mentioned during patient histories.

3) Clinical presentation
The initial scenario for AMI is a nonspecific acute abdomen 11,12 .Patients classically present with severe abdominal pain disproportionate to physical examination findings; nausea, vomiting, and diarrhea are common 11,12,67,68 .Abdominal distension and gastrointestinal bleeding with no apparent cause should be taken into account.However, as gastrointestinal symptoms have been frequent in COVID-19 patients in general 16 and may even precede respiratory symptoms 69 , they become even more nonspecific for AMI.Furthermore, all these clinical manifestations may be masked in those patients sedated in the ICU, the key to an early diagnosis being therefore a high level of clinical suspicion 11 .

4) Risk factors
Factors associated with a higher risk of thrombotic complications during COVID-19 are advanced age, male sex, obesity, cardiovascular diseases, hypertension, and diabetes 13,16,19 .However, as already seen, young patients without significant comorbidities are still subject to complications and high risk of death 70 .

Silva
Acute mesenteric ischemia and COVID-19: an integrative review of the literature 5) Complementary exams

Laboratory tests
Laboratory data, although nonspecific, can be of great value to raise the suspicion of AMI during the course of thromboinflammation mediated by SARS-Cov-2 11,68,71 .Metabolic acidosis with an elevated lactate level is one of the most common abnormalities 11,67,71 , but is not specific 71 .Hyperkalemia and hyperphosphatemia are usually late signs of intestinal infarction 67 .Leukocytosis is also frequent 11,67,69,71 and has been described as a marker of poor prognosis in COVID-19 16,18,19,69 .
D-dimer, a product of fibrin degradation, is also part of the AMI investigation 68,71 .Despite being very sensitive and not very specific, its significantly elevated values during COVID-19 denote a high thrombotic risk and are related to disease severity 13,15,18,19,72 .Lodigiani et al. demonstrated that D-dimer levels increased substantially during hospitalization of non-surviving patients in a large Italian hospital 73 .In addition to it, CAC is manifested by changes in platelet count, prolonged PT and/or aPTT, and increased fibrinogen, factor VIII, and FvW 13,16,18,70 .The study by Tang et al. observed that abnormalities in these coagulation parameters during COVID-19 are associated with a worse prognosis 74 .
Positive lupus anticoagulant can also be seen in a number of patients with COVID-19 34 .

Imaging exams
Imaging exams make a crucial contribution to the diagnosis of mesenteric ischemia 12,68 .Computed tomographic angiography is the first-line diagnostic modality and should be performed as soon as clinical suspicion arises 11,12,66,75 .In addition to being quick, accessible, and non-invasive 12,66,75 , it has high sensitivity (89.4%) and specificity (99.5%) 75 .The characteristic findings described in the literature and consistent with those identified during the review are: 1) filling defects in the lumen of mesenteric vessels indicating the existence of thrombi or emboli 12 ; 2) reduction or absence of mural enhancement 11,12,66 ; 3) intestinal wall thickening -the most sensitive but nonspecific indicator of ischemia 11,12,66,68 ; 4) "halo" or "target" appearance of the intestinal wall due to edema in the submucosal layer interspersed between the mucosa and muscle 11,12,66 ; 5) luminal dilation and a "paper-thin" wall 12,66 ; 6) intestinal pneumatosis, portomesenteric venous gas, and intraperitoneal free gas are signs of irreversible ischemia 11,12,66,68 ; 7) splenomegaly, ascites, and mesenteric fat stranding may also be present 11,12,66 ; 8) In NOMI, these intestinal signs are seen and usually occur in a discontinuous and segmental way, but the mesenteric vessels do not have thromboembolic occlusions 11,66 , as reported by two of the included studies 28,30 .
Angiography allows a simultaneous diagnostic and therapeutic approach.However, it is currently considered second-line due to its invasive character and low availability in health centers, being destined for endovascular management and cases of NOMI 12,66 .Plain X-rays and Ultrasonography are limited in cases of AMI and lack sensitivity and specificity, which is why they are rarely used 11,66-68 .

6) Treatment
Management of AMI involves restoration of mesenteric blood flow, with resection of the necrotic bowel 12 .The initial approach requires fluid resuscitation and aggressive correction of electrolyte abnormalities and acid-base imbalance 11,66,67 .Anticoagulation with heparin should be started in the absence of contraindications 11,66 and broad-spectrum antibiotics need to be administered due to bacterial translocation and increased risk of sepsis 11,12,66,67 .
Emergency laparotomy is indicated in patients with signs of peritonitis, infarction, or intestinal perforation 11,66 .It allows direct visualization of intestinal viability, resection of unviable loops, and early reestablishment of mesenteric blood flow 11,66 .
However, during this first surgical approach, doubts may remain regarding the ischemic involvement of some segments, thus, planned relaparotomy/ second-look is recommended as part of the management of AMI 11,66,67 .
It is usually performed within 24 to 48 hours of the first approach and, in addition to allowing the resection of initially unnoticed necrotic loops, it also avoids hasty resection of healthy loops by the first approach, reducing the chances of "short bowel syndrome" 11,67 .
The endovascular approach can be considered individually when there is no clear evidence of irreversible intestinal ischemia or in combination with conventional open surgery.Revascularization methods vary according to the etiopathogenesis of AMI 11,12,66,67 .
NOMI management is based on correcting the underlying cause of splanchnic vasoconstriction and resection of the necrotic bowel when identified.

7) Drug prophylaxis for CAC
Current evidence supports parenteral prophylactic anticoagulation in patients with COVID-19 in the absence of absolute contraindications and especially in the most critical cases 13,15,16,18,19,70 .The prognosis of patients who use heparin has been better than that of non-users 65 .In addition to its anticoagulant role, a certain anti-inflammatory potential associated with heparin may be able to attenuate the cytokine storm and endothelial damage during COVID-19 19 .
Extended thromboprophylaxis is also being advocated post-discharge from COVID-19 in certain cases, but there is still no consensus 13,16,70 .

8) Applicability
Given the severity of AMI and the increase in its incidence in the context of COVID-19, this study can serve as a warning to the multidisciplinary teams that deal with these patients.A general knowledge about the clinical presentation, laboratory alterations, and imaging findings will be able to raise the index of suspicion, allowing diagnosis and treatment as early as possible, to reduce the significant associated morbidity and mortality.

9) Study limitations
The results come primarily from reports, case series, and small retrospective studies, which undoubtedly increases the risk of publication bias.In addition, despite the concern to select studies with uniformity as to the description of data, there were differences: not all provided the same laboratory parameters, clear information about anticoagulation, and time of post-discharge follow-up of patients, consequently, no the actual associated mortality rate is known.
ischemia and are in line with what recent evidence has called COVID-19 Associated Coagulopathy (CAC) 13-15 .In response to the initial research question, we listed some mechanisms considered to be primarily responsible for the pathogenesis of this acute abdomen condition: a) Vascular endothelial injury and direct intestinal injury; b) Thromboinflammation; c) Dysregulation of the Renin Angiotensin Aldosterone System (RAAS); and d) Factors related to disease severity.

Furthermore, COVID- 19
is still under investigation and the evidence about it is still scarce, lacking in large studies, which makes it difficult to establish a reliable and well-understood relationship between it and mesenteric ischemia.Obviously, it would be beyond the capacity of this study to cover all the thrombotic potential linked to the new coronavirus.Therefore, answers about the general prevalence of thromboembolic complications resulting from COVID-19, pathophysiology, risk factors, safe use of anticoagulation, and better strategies for diagnosing and managing AMI in these cases should be left to future investigations by large prospective, multicentric, multinational studies.CONCLUSION A process of thromboinflammation and endothelial dysfunction belonging to SARS-CoV-2, together with the severity factors, are responsible for the development of AMI, as well as other thrombotic conditions.A high rate of clinical suspicion followed by early diagnosis and immediate treatment are essential for reducing the mortality associated with this surgical emergency.Multidisciplinary teams should be attentive to gastrointestinal signs and symptoms during the hospitalization of infected patients, with special attention to those in severe cases admitted to the ICU, and guide them after discharge to seek emergency care in the event of suspicious clinical manifestations.Cell counts, ionograms, and especially coagulation parameters and inflammatory markers need to be monitored and, when AMI is suspected, angiotomography should be performed as soon as possible.The goal of treatment is to reestablish mesenteric blood flow and resect the necrotic bowel.Finally, unless contraindicated, patients with COVID-19 should receive prophylactic anticoagulation as per current guidelines pending consensus through randomized controlled trials.
Tabela 1. shows the country of each study, number of patients and respective ages, gastrointestinal signs and symptoms, main abdominopelvic imaging findings by computed tomography, conduct, and outcome (hospital discharge or death).